Featured Article The Radioisotope Contributes Significantly to the Activity of Radioimmunotherapy Thomas A. Davis, 1 Mark S. Kaminski, 2 John P. Leonard, 3 Frank J. Hsu, 5 Mary Wilkinson, 6 Andrew Zelenetz, 4 Richard L. Wahl, 2 Stewart Kroll, 7 Morton Coleman, 3 Michael Goris, 1 Ronald Levy, 1 and Susan J. Knox 1 1 Stanford University, Stanford, California; 2 University of Michigan, Ann Arbor, Michigan; 3 Weill Medical College of Cornell University, and 4 Memorial Sloan Kettering Cancer Center, New York, New York; 5 Yale University, New Haven, Connecticut; 6 INOVA Fairfax Hospital, Fairfax, Virginia; and 7 Corixa Corporation, South San Francisco, California ABSTRACT Purpose: A multicenter, randomized study was under- taken to estimate the single agent activity of Tositumomab and to determine the contribution of radioisotope-labeling with 131 I to activity and toxicity by comparing treatment outcomes for Tositumomab and Iodine I 131 Tositumomab (BEXXAR) to an equivalent total dose of unlabeled Tositu- momab. Experimental Design: Seventy-eight patients with refrac- tory/relapsed non-Hodgkin’s lymphoma were randomized to either unlabeled Tositumomab or Iodine I 131 Tositumomab. Patients progressing after unlabeled Tositumomab could cross over to receive Iodine I 131 Tositumomab. The median fol- low-up at analysis was 42.6 months (range 1.9 to 71.5 months). Results: Responses in the Iodine I 131 Tositumomab versus unlabeled Tositumomab groups: overall response 55% versus 19% (P  0.002); complete response 33% versus 8% (P  0.012); median duration of overall response not reached versus 28.1 months (95% confidence interval: 7.6, not reached); median duration of complete response not reached in either arm; and median TTP 6.3 versus 5.5 months (P  0.031), respectively. Of the patients who had a complete response after initial Iodine I 131 Tositumomab therapy, 71% (10 of 14) continued in complete response at 29.8 to 71.1 months. Two patients who achieved a complete response after unlabeled Tositumomab had ongoing re- sponses at 48.1 to 56.9 months. Nineteen patients received Iodine I 131 Tositumomab crossover therapy. Responses after crossover versus prior response to unlabeled Tositu- momab were as follows: complete response rates of 42% versus 0% (P  0.008); overall response 68% versus 16% (P  0.002); median durations of overall response 12.6 versus 7.6 months (P  0.001); and median TTP 12.4 versus 5.5 months (P  0.01), respectively. Hematologic toxicity was more severe and nonhematologic adverse events were more frequent after Iodine I 131 Tositumomab than after Tositumomab alone. Elevated thyrotropin occurred in 5% of patients. Seroconversion to human antimurine antibody after Iodine I 131 Tositumomab, unlabeled Tositumomab, and Iodine I 131 Tositumomab-crossover was 27%, 19%, and 0%, respectively. Conclusions: Unlabeled Tositumomab showed single agent activity, but in this direct comparison, all of the ther- apeutic outcome measures were significantly enhanced by the conjugation of 131 I to Tositumomab. INTRODUCTION Agents targeting the CD20 antigen have shown significant activity in B-cell lymphomas. Rituximab, a chimeric mono- clonal antibody (MAb) against CD20, induces response in 50% of patients with relapsed disease (1). The IgG2 a murine MAb, Tositumomab, also specifically binds to the CD20 antigen and has been shown to have in vitro and in vivo activity against human B-cell non-Hodgkin’s lymphoma (NHL) (2, 3). On bind- ing to the CD20 antigen, both MAbs evoke immune effector functions as follows: antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity as well as apoptosis (4 – 6). The efficacy of antibody therapy seems to be enhanced by conjugation of the MAb with a radionuclide (7, 8). However, the radioisotope also adds to the toxicity profile of these agents through marrow suppression and possible marrow dysplasia. The radiation emission from the isotope can provide not only direct toxicity to the cell bound by the antibody, but also toxicity to neighboring tumor and normal cells through “cross-fire radi- ation” that damages cells that are not accessible to the MAb, Received 5/26/04; revised 7/8/04; accepted 7/23/04. Grant support: Grant PPG CA33399 from the NIH, Human Health Service Grant MOI-RR00070 General Clinical Research Centers, Na- tional Center for Research Resources, NIH. T. Davis was supported by a Clinical Associate Physician Award from the General Clinical Re- search Centers of the NIH. The clinical study was supported in part by research grants from Coulter Pharmaceuticals. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: R. Levy is an American Cancer Society Clinical Research Pro- fessor. Corixa Corporation and GlaxoSmithKline provided collaborative support and assistance to the authors for preparation of the manuscript. Several of the authors (M. Kaminski, R. Wahl, and S. Kroll) have de- clared a financial interest in a company for which potential product was studied in the present work. One of the authors (S. Kroll) is used by a company for which potential product was studied in the present work. Requests for reprints: Thomas Davis, EPN 7025, 6130 Executive Boulevard, Rockville, MD 20892. Phone: (301) 496-2522; Fax: (301) 402-0557; E-mail: davisth@mail.nih.gov. ©2004 American Association for Cancer Research. 7792 Vol. 10, 7792–7798, December 1, 2004 Clinical Cancer Research Research. on January 9, 2016. © 2004 American Association for Cancer clincancerres.aacrjournals.org Downloaded from